@article{RuthKS2016,
title = {Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health},
author = {Ruth, K. S.
Beaumont, R. N.
Tyrrell, J.
Jones, S. E.
Tuke, M. A.
Yaghootkar, H.
Wood, A. R.
Freathy, R. M.
Weedon, M. N.
Frayling, T. M.
Murray, A.},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26732621},
year = {2016},
date = {2016-01-07},
journal = {Hum Reprod},
abstract = {STUDY QUESTION: How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health? SUMMARY ANSWER: The T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis. WHAT IS KNOWN ALREADY: The FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle. MAIN RESULTS AND THE ROLE OF CHANCE: The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12-0.20; P = 6 x 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 x 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 x 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 x 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 x 10(-9)). LIMITATIONS, REASONS FOR CAUTION: The data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as 'irregular'). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect. WIDER IMPLICATIONS OF THE FINDINGS: We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.},
keywords = {FSH, menopause, menstrual cycle},
pubstate = {published},
tppubtype = {article}
}

STUDY QUESTION: How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health? SUMMARY ANSWER: The T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis. WHAT IS KNOWN ALREADY: The FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle. MAIN RESULTS AND THE ROLE OF CHANCE: The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12-0.20; P = 6 x 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 x 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 x 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 x 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 x 10(-9)). LIMITATIONS, REASONS FOR CAUTION: The data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as 'irregular'). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect. WIDER IMPLICATIONS OF THE FINDINGS: We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.

We identified 54 common signals and 2 independent low frequency signals at 44 loci. Both low frequency variants were at loci where there were also common variant associations. Two thirds of the menopause associated loci include genes involved in the DNA damage response, including the first reported common variant in BRCA1. Fifteen proteins from genes at other loci are known to interact with BRCA1, particularly in the BRCA1 A complex. Five of the loci contained genes in which monogenic mutations cause hypogonadotrophic hypogonadism and delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan.

We used a mendelian randomization approach to assess the relationship between menopause timing and breast cancer in ~45,000 breast cancer cases and ~45,000 controls from the Breast Cancer Association Consortium (BCAC). A higher genetic risk score for later menopause was associated with increased breast cancer risk, indicating a causal relationship between menopause timing and breast cancer risk, though this did not appear to be mediated through the DNA damage response pathway.

We provide robust evidence for the association of 54 independent, common and low frequency variants which explain 6% of the variance in menopause timing and highlight a role for the DNA damage response pathway in maintaining ovarian reserve.},
keywords = {871, menopause},
pubstate = {published},
tppubtype = {presentation}
}

Timing of menopause has been associated with numerous adverse health outcomes, including infertility, cancer, osteoporosis, cardiovascular disease and diabetes. Previous genome wide association studies (GWAS) identified 18 common variants, which explain ~3% of the variance in timing of natural menopause. In the current study we have nearly doubled our sample size from 45,000 to 70,000 and included low frequency variants in addition to common variants. We have replicated our findings in 27,000 women from the UKBiobank study.

We identified 54 common signals and 2 independent low frequency signals at 44 loci. Both low frequency variants were at loci where there were also common variant associations. Two thirds of the menopause associated loci include genes involved in the DNA damage response, including the first reported common variant in BRCA1. Fifteen proteins from genes at other loci are known to interact with BRCA1, particularly in the BRCA1 A complex. Five of the loci contained genes in which monogenic mutations cause hypogonadotrophic hypogonadism and delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan.

We used a mendelian randomization approach to assess the relationship between menopause timing and breast cancer in ~45,000 breast cancer cases and ~45,000 controls from the Breast Cancer Association Consortium (BCAC). A higher genetic risk score for later menopause was associated with increased breast cancer risk, indicating a causal relationship between menopause timing and breast cancer risk, though this did not appear to be mediated through the DNA damage response pathway.

We provide robust evidence for the association of 54 independent, common and low frequency variants which explain 6% of the variance in menopause timing and highlight a role for the DNA damage response pathway in maintaining ovarian reserve.

@article{Guo2014,
title = {Association of physical activity with body size and composition in pre- and postmenopausal UK Biobank women: a cross-sectional study},
author = {W Guo and KE Bradbury and V Beral and GK Reeves and TJ Key},
url = {http://jech.bmj.com/content/68/Suppl_1/A23.1.abstract},
year = {2014},
date = {2014-09-01},
journal = {Journal of Epidemiology and Community Health},
volume = {68},
number = {1},
pages = {A23},
abstract = {Background UK Biobank provides a unique opportunity to study the association between physical activity and various body composition measures. We examined the relationship between physical activity and both total and central body fat separately for premenopausal and postmenopausal women, since previous studies suggest menopause-related changes in fat accumulation and distribution. We also assessed whether higher overall levels of physical activity were associated with lower fat percentage and absolute mass, for a given body mass index category.

Methods A total of 40,006 premenopausal and 81,407 postmenopausal generally healthy women aged 39–70 in UK Biobank were included in this cross-sectional study. Self-reported information on frequency and duration of low, moderate, and vigorous physical activity was collected by touchscreen questionnaire. Physical activity was calculated as metabolic equivalent task hours per week (MET-hours/week) and participants were categorised as having low (<10 MET-hours/week), moderate (10–49.9 MET-hours/week), and high (>50 MET-hours/week) levels of physical activity based on International Physical Activity Questionnaire guidelines. Body size was measured by trained technicians. Overall adiposity was assessed by body mass index (BMI) as well as body fat percentage and mass (bioelectrical impedance). Central adiposity was represented using waist circumference, waist-hip ratio, trunk fat mass, and trunk fat percentage. Associations between body composition measures were analysed using multiple linear regression. We adjusted for age at recruitment, educational qualifications, quintiles of Townsend deprivation index, parity, hormone replacement therapy use, and smoking status. Stata 13 (StataCorp LP, Texas, USA) was used for all statistical analyses.

Results The median (IQR) physical activity was 29.1 MET-hours/week (13.9–54.2) for premenopausal and 31.8 MET-hours/week (15.5–62.0) for postmenopausal women. All measures of total and central adiposity decreased with increasing physical activity. An increase in physical activity from low to moderate or moderate to high was associated with an average 0.94 unit lower BMI (95% CI 0.88–1.01) for premenopausal and 0.82 unit lower BMI (95% CI 0.77–0.86) for postmenopausal women. For a given BMI category, those with a moderate level of physical activity had a lower body fat percentage than those with a low level and the group with the highest level of physical activity had the lowest body fat percentage for a given BMI category.

Background UK Biobank provides a unique opportunity to study the association between physical activity and various body composition measures. We examined the relationship between physical activity and both total and central body fat separately for premenopausal and postmenopausal women, since previous studies suggest menopause-related changes in fat accumulation and distribution. We also assessed whether higher overall levels of physical activity were associated with lower fat percentage and absolute mass, for a given body mass index category.

Methods A total of 40,006 premenopausal and 81,407 postmenopausal generally healthy women aged 39–70 in UK Biobank were included in this cross-sectional study. Self-reported information on frequency and duration of low, moderate, and vigorous physical activity was collected by touchscreen questionnaire. Physical activity was calculated as metabolic equivalent task hours per week (MET-hours/week) and participants were categorised as having low (<10 MET-hours/week), moderate (10–49.9 MET-hours/week), and high (>50 MET-hours/week) levels of physical activity based on International Physical Activity Questionnaire guidelines. Body size was measured by trained technicians. Overall adiposity was assessed by body mass index (BMI) as well as body fat percentage and mass (bioelectrical impedance). Central adiposity was represented using waist circumference, waist-hip ratio, trunk fat mass, and trunk fat percentage. Associations between body composition measures were analysed using multiple linear regression. We adjusted for age at recruitment, educational qualifications, quintiles of Townsend deprivation index, parity, hormone replacement therapy use, and smoking status. Stata 13 (StataCorp LP, Texas, USA) was used for all statistical analyses.

Results The median (IQR) physical activity was 29.1 MET-hours/week (13.9–54.2) for premenopausal and 31.8 MET-hours/week (15.5–62.0) for postmenopausal women. All measures of total and central adiposity decreased with increasing physical activity. An increase in physical activity from low to moderate or moderate to high was associated with an average 0.94 unit lower BMI (95% CI 0.88–1.01) for premenopausal and 0.82 unit lower BMI (95% CI 0.77–0.86) for postmenopausal women. For a given BMI category, those with a moderate level of physical activity had a lower body fat percentage than those with a low level and the group with the highest level of physical activity had the lowest body fat percentage for a given BMI category.

Conclusion Both total and central adiposity decrease with increasing levels of physical activity. For a given BMI category, greater physical activity is associated with decreased body and trunk fat mass and percentage.